Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracranial malignant gliomas are sequestered from the immune system yet are associated with broad suppression of host immunocompetence. Immune system dysfunction in patients with gliomas seems to be related to inhibitory mediators produced by glioma cells. We investigated the physiological roles of glioma-derived interleukin (IL)-10 in Class II expression of monocytes, cytokine secretion from lymphocytes, and T cell proliferation in vitro. We could detect the messenger ribonucleic acid transcript of IL-10 in four gliomas by the reverse-transcribed polymerase chain reaction. Glioma-derived IL-10 greatly down-regulated human lymphocyte antigens-DR expression on monocytes. The inhibitory effect of IL-10 on interferon-gamma and tumor necrosis factor-alpha was neutralized by the anti-IL-10 monoclonal antibody; however, the inhibitory effect on IL-2 was not neutralized. Next, supernatants of glioma cells remarkably suppressed T cell proliferation in a dose-dependent fashion; however, this inhibitory effect was not restored by adding anti-IL-10 monoclonal antibodies. The supernatant also inhibited the allocytolytic activity of lymphocytes that were not neutralized by anti-IL-10 monoclonal antibody. IL-10 plays an important role in cytokine synthesis; nevertheless, impaired T cell responsiveness cannot be solely explained by glioma-derived IL-10.
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PMID:Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro. 858 57

To effectively induce apoptosis in human glioma cells, we tried to transfer the tumor necrosis factor (TNF)-alpha gene into glioma cells to produce TNF-alpha locally in these cells. The stable transfectants of three glioma cells (U251-SP, U251-MG, and T98G) were resistant to exogenous TNF-alpha, but their cell surface expression of the Fas antigen was dramatically enhanced by about 10 to 100-fold as compared with untransfected glioma cells exposed to exogenous TNF-alpha. The Fas antigen is a transmembrane cytokine receptor protein of the nerve growth factor/TNF receptor superfamily. Although the untransfected glioma cells tested were resistant to anti-Fas antibody-mediated apoptosis, the TNF-alpha gene-transfected glioma cells exhibited high susceptibility to anti-Fas antibody-mediated apoptosis. Thus, TNF-alpha gene transfer combined with anti-Fas antibodies may be useful for the treatment of malignant glioma.
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PMID:Tumor necrosis factor-alpha gene transfer augments anti-Fas antibody-mediated apoptosis in human glioma cells. 864 93

With the aim of developing an effective immunotherapy for malignant glioma, glioma cells were incubated with tumor necrosis factor-alpha (TNF-alpha) to increase their susceptibility to lysis by lymphokine-activated killer (LAK) cells. Treatment with exogenous TNF-alpha induced the expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of glioma cells. In addition, the cytolytic activity of LAK cells toward exogenous TNF-alpha treated glioma cells was significantly greater than LAK cell activity toward untreated glioma cells. This increase in cytolytic activity was blocked by anti-ICAM-1 monoclonal antibodies (MAb). Furthermore, co-treatment with a bifunctional antibody (BFA) composed of anti-CD3 (UCHT1) and antiglioma (G-22) antibodies synergistically increased the cytolytic activity of LAK cells towards TNF-alpha-treated glioma cells. These results indicate that a combination of exogenous TNF-alpha and anti-CD3/antiglioma BFA may provide an effective modified adoptive immunotherapy for patients with malignant glioma.
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PMID:Cytolysis of malignant glioma cells by lymphokine-activated killer cells combined with anti-CD3/antiglioma bifunctional antibody and tumor necrosis factor-alpha. 866 24

In an effort to obtain a useful in vitro model possessing some of the properties of the blood-brain barrier, we have investigated the properties and interactions of immortalized cell lines. Immortalised human umbilical vein endothelial cells (HUVEC-304), in co-culture with rat C6 glioma cells in a two-chambered assembly, form tight junctional complexes, and develop a permeability barrier having a high transcellular electrical resistance. The endothelial cells generate a barrier with greatest integrity in the presence of glioma cells, or in the presence of glioma cell conditioned medium. Under these conditions, the endothelial cells also display pronounced structural changes which do not occur in the absence of glioma cells. Morphological alterations include a flattening of cell shape from a cuboidal-type to a squamous-type of appearance, and a re-organization of F-actin microfilaments. The integrity of the barrier can be reversibly disrupted by osmotic shock or by tumor necrosis factor-alpha (TNF-alpha). We interpret these observations to indicate that co-cultures of immortalized vascular endothelial and C6 glioma cells provide a model for the investigation of cell-cell interactions required for the generation of a barrier having several properties of the blood-brain barrier.
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PMID:Properties of an immortalised vascular endothelial/glioma cell co-culture model of the blood-brain barrier. 869 44

We investigated the expression of granulocyte colony-stimulating factor (G-CSF), G-CSF mRNA, and G-CSF receptor mRNA in astrocytoma cell lines, G-CSF in astrocytoma cyst fluid, and the effect of recombinant G-CSF on the proliferation of astrocytoma cells in vitro and in vivo. We first examined supernatants from astrocytoma cell lines for the presence of G-CSF by ELISA. G-CSF was expressed by 6 of 14 astrocytoma cell lines constitutively, and, was detected after stimulation with tumor necrosis factor-alpha (TNF-alpha) in four of eight cell lines which did not produce G-CSF constitutively. G-CSF mRNA was detected by reverse-transcriptase polymerase chain reaction (RT-PCR) in all cell lines studied, suggesting that astrocytoma cells have the potential to produce G-CSF. We also analyzed the presence of G-CSF by ELISA in five astrocytoma cyst fluids. G-CSF was detected in one case. Although, in vitro study, the growth of glioma cells was not affected by rG-CSF, in a mouse model, the administration of G-CSF significantly shortened the time to tumor appearance and accelerated tumor growth. These data suggest that G-CSF has a stimulatory effect on the proliferation of astrocytoma cells in vivo through the mediation of host factors.
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PMID:Granulocyte colony-stimulating factor (G-CSF) production by astrocytoma cells and its effect on tumor growth. 869 23

Oligodendrocytes (OLs) and their myelin membranes are the apparent injury targets in the putative human autoimmune disease multiple sclerosis. The basis for this selective injury remains to be defined. OLs in vitro have been shown to be susceptible to both tumor necrosis factor (TNF) and non-TNF-dependent immune effector mechanisms. The former involves initial nuclear injury (apoptosis); the latter, when mediated by activated T cells, involves initial cell membrane injury (lysis). In the current study, we determined whether human adult CNS-derived OLs could be protected from the above immune effector mechanisms by selected neurotrophic factors (CNTF, BDNF, NGF, NT-3, and NT-4/5) or cytokines demonstrated to protect from human or experimental autoimmune demyelinating diseases (beta-interferon [IFN], IL-10, and TGF-beta). Nuclear injury was assessed in terms of DNA fragmentation using a DNA nick-end-labelling technique; cell membrane injury was assessed by lactate dehydrogenase or chromium 51 release. MTT and cell counting assays were used to assess cell viability and cell loss, respectively. Amongst the neurotrophic factors and cytokines tested, only CNTF significantly protected the OLs from TNF-mediated injury. CNTF also protected the OLs from serum deprivation-induced apoptosis. CNTF, however, did not protect the OLs from injury induced by activated CD4+ T cells. CNTF also did not protect human fetal cortical neurons from serum deprivation or TNF-induced DNA fragmentation, nor did it protect the U251 human glioma cell line from DNA fragmentation induced by a combination of TNF and reduced serum concentration in the culture media. Our results indicate that potential protective effects of neurotrophic factors or cytokines on neural cell populations can be selective both for cell type involved and mechanism of immune-mediated injury. CNTF is the protective factor selective for nuclear-directed injury of OLs.
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PMID:Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury. 871 18

The morphological changes in the vascular endothelium caused by the administration of tumor necrosis factor-alpha (TNF-alpha) were studied in an experimental model of rat brain tumors. Wistar rats bearing implanted C6 glioma received human natural-type TNF-alpha (1.7 x 10(5) U/m2) through the carotid artery and were sacrificed 3 or 24 hours later. The endothelial cells of the tumor blood vessels, demonstrated by the immunoreaction to factor VIII-related antigen, were enlarged after TNF-alpha administration. Morphometry demonstrated that the nuclei of these endothelial cells were also increased in size. The endothelial cells in the brain remote to the tumor were not affected. An in vitro binding study demonstrated that TNF-alpha binding sites were distributed in the vascular endothelial cells within the tumor but not in the brain remote to the tumor. The selective effect of TNF-alpha on the tumor blood vessels in experimental brain tumors may be related to the selective distribution of the TNF-alpha binding site.
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PMID:Morphological effects of tumor necrosis factor-alpha on the blood vessels in rat experimental brain tumors. 874 70

The possibility that 5,6,7,8-tetrahydrobiopterin (BH4) biosynthesis is stimulated in glial cells by treatment with lipopolysaccharide (LPS) and tumor necrosis factor (TNF-alpha) was examined in the astrocyte-derived C6 glioma cell line. Under basal culture conditions BH4 levels were found to be at the limit of detection. Concurrent treatment with 10 micrograms/ml LPS and 50 ng/ml TNF-alpha caused a time-dependent 13-fold increase in the levels of BH4. This treatment paradigm also induced nitric oxide synthase activity, as evidenced by increased levels of nitrite, an oxidized metabolite of NO, in the culture medium. LPS and TNF-alpha treatment led to a 25-fold increase in GTPCH enzyme activity, the first and rate-limiting enzyme in BH4 synthesis, and a corresponding 23-fold increase in GTPCH protein levels. Northern blot analysis showed that increased levels of GTPCH mRNA preceded changes in GTPCH protein, GTPCH enzyme activity and BH4 levels and reached a maximal of 44-fold that was sustained for at least 48 h. These results demonstrate that LPS and TNF-alpha stimulate de-novo BH4 biosynthesis and suggest that C6 cells offer a model system for studying the molecular events that control the induction of GTPCH gene expression and BH4 synthesis in glial cells.
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PMID:Tetrahydrobiopterin biosynthesis in C6 glioma cells: induction of GTP cyclohydrolase I gene expression by lipopolysaccharide and cytokine treatment. 888 40

The effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the expression of macrophage colony-stimulating factor (M-CSF), leukemia inhibitory factor (LIF), and tumor necrosis factor-alpha (TNF-alpha) genes in primary rat astrocytes and C6 glioma cells was examined. The results show that the hormone differentially regulates the cytokine mRNA in the two cell types. 1,25-(OH)2D3 augments M-CSF and LIF mRNA in C6 glioma cells, while lipopolysaccharide (LPS) has minimal effects. When LPS and 1,25-(OH)2D3 are used in combination, a strong synergistic effect upon the induction of M-CSF and LIF genes is observed. No TNF-alpha transcript has been detected in C6 glioma cells under any stimulus conditions used. In contrast, 1,25-(OH)2D3 has no pronounced effect on M-CSF, LIF, and TNF-alpha transcripts in primary astrocytes when used as a sole stimulus, while treatment with LPS strongly enhances the levels of the three cytokines. However, when 1,25-(OH)2D3 is used in combination with LPS, a partial reduction in LPS-induced levels of M-CSF and TNF-alpha mRNA is observed. The overall results indicate that genes coding for some inflammatory cytokines obey distinct regulatory mechanisms in C6 cells and in primary astrocytes. They also suggest that 1,25-(OH)2D3, by altering the response of astrocytes to an inflammatory stimulus, could participate in the regulation of the CNS immune response.
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PMID:Differential expression of M-CSF, LIF, and TNF-alpha genes in normal and malignant rat glial cells: regulation by lipopolysaccharide and vitamin D. 893 75

The pro-inflammatory and blood-brain barrier (BBB) effects of intratumoral (IT) injection of human recombinant tumor necrosis factor-alpha (rTNF-alpha) were studied in the Fischer rat RT-2 glioma model. Animals received a single stereotaxic injection of either 6 x 10(4) U rTNF-alpha or excipient (vehicle) into the center of an intracerebrally implanted glioma. In order to demonstrate any effects rTNF-alpha might have on the BBB, studies were conducted using endogenous IgG (150 kD) as a tracer. Forty-eight hours following injection of excipient, a margin of peritumoral IgG extravasation was observed while rats treated with 6 x 10(4) U rTNF-alpha showed a dense and extensive IgG extravasation involving both hemispheres. Histological examination revealed that an IT rTNF-alpha injection induced leukocytic adherence, neutrophilic cuffing and infiltration throughout the lesion from 12 to 72 h after injection. These histological observations were supported by quantification of cerebral myeloperoxidase (MPO) levels which indicated a significant increase in neutrophils over the excipient recipients at 4 and 12 h. These MPO levels contrasted with our earlier studies in normal rats which revealed no significant difference in tissue MPO levels following injection of excipient or rTNF-alpha. In addition, when MPO levels in tumor models and normal rats receiving TNF were compared, a significantly greater presence of neutrophils was seen in tumor models at 12 h post-TNF injection. We believe that the increased inflammatory response seen in a progressing glioma compared to normal brain may be the result of decreased resistance to leukocytic infiltration due to increased vascular surface area, the lack of infiltration-resistant perivascular basement membrane, and/or increased extracellular space.
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PMID:Effects of an intratumoral injection of human recombinant tumor necrosis factor-alpha on cerebrovascular permeability and leukocytic infiltration in a rat glioma model. 900 60


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